Breast cancer is currently the most frequently occurring cancer and the leading causes of cancer-related death among women in the world. Single nucleotide polymorphism (SNP) is the most common form of human genetic variation, and may contribute to individual’s susceptibility to cancer, however, the underlying molecular mechanism is unknown. Previous study suggested that some variants, especially those in the promoter regions of genes, may affect either the expression or activity levels of enzymes
[59–61] and therefore may be mechanistically associated with cancer risk. Previous studies on the relationship between MTHFR Ala222Val polymorphisms and BC risk were contradictory. These inconsistent results are possibly because of a small effect of the polymorphism on BC risk or the relatively low statistical power of the published studies. Hence, the meta-analysis was needed to provide a quantitative approach for combining the results of various studies with the same topic, and for estimating and explaining their diversity.
Meta analysis has great power for elucidating genetic factors in cancer. On the bases of the character of cancer, the effect of one genetic component on the development of the disease can be easily masked by other genetic and environmental factors. A meta-analysis potentially investigates a large number of individuals and can estimate the effect of a genetic factor on the risk of the disease
[62, 63]. The present study included data from 51 association studies that had investigated the relationship between the MTHFR Ala222Val polymorphism and BC.
This present meta-analysis, including 20,907 cases and 23,905 controls, concerned the Ala222Val polymorphism of MTHFR gene and BC risk. In the meta-analysis, we found that the variant genotypes of the MTHFR Ala222Val polymorphisms were significantly associated with BC risk. Simultaneously, the same results presented in stratified analysis by ethnicity. We found that the variant genotype of the MTHFR Ala222Val polymorphism, in Asian populations, was associated with significant increase in BC risk. Although the MTHFR Ala222Val polymorphism may be associated with DNA repair activity, no significant association of the variant genotype with BC risk was found in Caucasian and Mixed populations, suggesting the influence of the genetic variant may be masked by the presence of other as-yet unidentified causal genes involved in colorectal cancer.
Some limitations of this meta-analysis should be acknowledged. First, our result was based on unadjusted estimates, while a more precise analysis should be conducted adjusted by other factors like diet habit, smoking, drinking status, environmental factors and so on. Second, in the subgroup analyses by ethnicity, relatively limited study numbers to perform ethnic subgroup analysis of mixed populations. Moreover, there are no American and African-American descent populations. Thus, additional studies are warranted to evaluate the effect of this functional polymorphism on BC risk in different ethnicities, especially in American, African-American and Mixed populations. In addition, our analysis did not consider the possibility of gene-gene or SNP-SNP interactions or the possibility of linkage disequilibrium between polymorphisms.
Despite of some limitations, this meta-analysis provided evidence of the association between the MTHFR Ala222Val polymorphisms and BC risk, supporting the hypothesis that MTHFR Ala222Val polymorphism contributes to overall BC risk. In subgroup analysis, the same results were found in Asian populations. In order to verify our findings, well-designed studies including different ethnic groups with a careful matching between cases and controls should be considered in future association studies to confirm the results from our meta-analysis. Moreover, further evaluating the effect of gene-gene and gene-environment interactions on the Ala222Val polymorphism and BC risk are necessary.